Abnormal thyroid hormone receptor function is often associated with some forms of human disease. Thyroid hormone receptor responds to circulating thyroid hormone and through interactions with its cognate DNA binding elements, changes in gene expression ensue. In addition to thyroid hormone receptor co-repressor and co-activator proteins. Together with the thyroid hormone receptor, these help to form protein DNA complexes, which alter gene transcription. The thyroid hormone receptor is made of two domains, one that binds DNA and one that binds hormone. Our interest is in understanding the structure and response of the receptor to binding protein partners and thyroid hormone or its analogs. Though they would be medically important, no antagonists of thyroid hormone receptor are known. Identification and synthesis of thyroid hormone antagonists would provide tools for understanding the normal and abnormal response of the thyroid hormone antagonists would provide tools for understanding the normal and abnormal response of the thyroid hormone receptors. We will determine the structural and the dynamic response of thyroid hormone receptor to binding partners of the hormone- binding domain by NMR and X-ray crystallography. Antagonists for thyroid hormone and antagonists for co-activator for co-activator binding will be identified. These molecules could have therapeutic value in human disease or become useful biological tools.